Functional C1q deficiency in a systemic lupus erythematosus patient with a concurrent somatic TNFAIP3 variant

Early identification of SLE patients with causative genetic variants may inform precision treatment strategies by revealing actionable biological pathways. In a refractory SLE patient harboring a somatic TNFAIP3 variant, we sought additional pathogenic variants and disease mechanisms. The patient’s medical records were collected. Whole-exome sequencing (WES) and droplet digital polymerase chain reaction (PCR) was performed to detect pathogenic variants and the variant allele frequency. Enzyme-linked immunosorbent assay and C1q reconstitution assay were conducted to assess the complement components. Bulk RNA sequencing and quantitative PCR were performed to explore the activation of inflammatory pathways. A 4-year-old girl with recurrent fever, arthritis, chilblain-like rashes, recurrent seizures, multiple positive autoantibodies and intracranial calcifications was referred to our hospital. Initial WES found a somatic pathogenic TNFAIP3 variant, suggesting the diagnosis of haploinsufficiency of A20 (HA20), which could account for the recurrent fever. However, the patient did not respond well to the first-line TNF inhibitors for HA20, prompting further genetic analysis. And a novel homozygous variant in C1QB was found. Complement assays showed functional C1q deficiency despite normal C1q levels. RNA sequencing revealed strong type I interferon signature in the patient, which was suppressed following treatment with the tyrosine kinase 2 inhibitor deucravacitinib. Fresh frozen plasma (FFP) infusions restored complement hemolytic activity. Combination therapy with FFP and deucravacitinib was associated with clinical stabilization and successful steroid tapering. We report a SLE case due to a novel C1QB variant causing functional C1q deficiency without reducing protein levels, with targeted C1q therapy showing efficacy. The co-existing somatic TNFAIP3 variant might contribute to part of the phenotype, such as recurrent fever.